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1.  East Ireland 1980-1994: epidemiology of neural tube defects 
STUDY OBJECTIVE: The objective of the study was to describe the epidemiology of neural tube defects (NTD) in the eastern region of Ireland using the EUROCAT register of congenital malformations. DESIGN, SETTING AND PATIENTS: EUROCAT registries monitor the prevalence of congenital anomalies in defined populations using multiple sources for case ascertainment. All cases of NTD on the Dublin EUROCAT register born between 1980 and 1994 were extracted and analysed. The crude birth prevalence rate for all NTD, spina bifida, anencephaly and encephalocoele were calculated for each year. Parameters measured were: sex ratio, stillbirth rate, proportion of low birth-weight babies (< 2500 g) and the proportion who were premature (< 37 weeks gestation). MAIN RESULTS: Of 821 NTD cases, 419 (51.0%) had spina bifida, 322 (39.2%) had anencephaly, 69 (8.4%) had encephalocoele and 11 (1.3%) were iniencephalic. The crude birth prevalence of NTD decreased fourfold from 46.9/10,000 births in 1980 to 11.6/10,000 in 1994. The downward trend ceased during the early 1990's. Younger mothers had significantly higher rates of NTD affected births. Twenty two per cent of NTD cases had additional non-central nervous system anomalies. In 40 cases, there was a previous family history of NTD in siblings. Seasonal effects in birth prevalence were observed. Birth notification was the most frequent mechanism of ascertainment. CONCLUSION: There was a marked fall in the birth prevalence of NTD during the 15 year period. This change was real and not accounted for by pre-natal screening and diagnostic practises with termination of pregnancy, which is not legally permissible in Ireland. Dietary factors may have had an influence. Rates of NTD in this region are still higher than many other parts of Europe. Primary prevention strategies through increased folic acid intake are necessary to further reduce NTD affected births.
 
PMCID: PMC1756811  PMID: 10656087
2.  Effects and safety of periconceptional folate supplementation for preventing birth defects 
Background
It has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear.
Objectives
This review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies.
Selection criteria
We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity.
Data collection and analysis
We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy.
Main results
Five trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term.
We found no evidence of short-term side effects.
Authors’ conclusions
Folic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects.
doi:10.1002/14651858.CD007950.pub2
PMCID: PMC4160020  PMID: 20927767
Dietary Supplements; Folic Acid [* administration & dosage]; Neural Tube Defects [* prevention & control]; Randomized Controlled Trials as Topic; Vitamin B Complex [* administration & dosage]; Female; Humans; Infant; Pregnancy
3.  The maternal folate hydrolase gene polymorphism is associated with neural tube defects in a high-risk Chinese population 
Genes & Nutrition  2012;8(2):191-197.
Folate hydrolase 1 (FOLH1) gene encodes intestinal folate hydrolase, which regulates intestinal absorption of dietary folate. Previous studies on the association between polymorphisms rs202676 and rs61886492 and the risk of neural tube defects (NTDs) were inconclusive. A case–control study of women with NTD-affected pregnancies (n = 160) and controls (n = 320) was conducted in the Chinese population of Lvliang, a high-risk area for NTDs. We genotyped the polymorphic sites rs202676 and rs61886492 and assessed maternal plasma folate and total homocysteine (tHcy). Our results showed that in case group, plasma folate concentrations were 18 % lower compared with those of control group (8.32 vs. 6.79 nmol/L, p = 0.033) and tHcy concentrations were 17 % higher (10.47 vs. 12.65 μmol/L, p = 0.047). Almost all samples had the rs61886492 GG genotype (99.78 %). The result showed that the frequency of GG genotype in rs202676 was significantly higher in group with multiple NTDs than in controls (p = 0.030, OR = 2.157, 95 % CI, 1.06–4.38). The multiple-NTD group showed higher maternal plasma concentrations of tHcy (10.47 vs. 13.96 μmol/L, p = 0.024). The GG genotype of rs202676 had a lower maternal folate and higher tHcy concentrations than other genotypes with no significant differences. The result of structural prediction indicated that this variation might change the spatial structure of the protein. These results suggested that the maternal polymorphism rs202676 was a potential risk factor for multiple NTDs in this Chinese population. The allele G might affect maternal plasma folate and tHcy concentration.
doi:10.1007/s12263-012-0309-3
PMCID: PMC3575888  PMID: 22918695
Association study; Chinese population; FOLH1; Neural tube defects; Single-nucleotide polymorphism
4.  Effects of differences in serum total homocysteine, folate, and vitamin B12 on cognitive impairment in stroke patients 
BMC Neurology  2014;14:217.
Background
Vascular cognitive impairment-no dementia (VCIND) refers to the early or mild cognitive impairment induced by cerebral vascular injury. Research shows that serum total homocysteine (tHcy) level is an independent risk factor for cerebral vascular disease and may be closely related to cognitive function.Current studies on the tHcy level in VCIND patients are limited, and the relationship of tHcy with cognitive function remains unclear. This study aims to investigate the tHcy levels in patients with VCIND and to determine their correlation with cognitive function, as well as to provide useful clues for preventing and treating VCIND.
Methods
The tHcy, folate, and vitamin B12 levels in 82 patients with VCIND were reviewed retrospectively and compared with those of 80 stroke patients without cognitive impairment and 69 healthy controls by using the Montreal Cognitive Assessment (MoCA) scale and the event-related potential P300 to evaluate cognitive function.
Results
The tHcy levels in the VCIND group were higher than those in the other two groups, whereas the folate and Vitamin B12 levels in the VCIND group were lower than those of the other two groups. The tHcy levels in the stroke group were higher than those in the control group, and the folate and vitamin B12 levels in the stroke group were lower than those in the control group. The patients in the VCIND group with high tHcy exhibited lower MoCA scores and prolonged P300 latency than those in with normal tHcy. Correlation analysis showed that tHcy level is positively correlated with P300 latency period and negatively correlated with MoCA score.
Conclusion
The tHcy levels were significantly higher and the vitamin B12 and folate levels were significantly lower in the patients with VCIND than those in the other groups. The high tHcy levels in the VCIND patients may be correlated with impaired cognitive function.
doi:10.1186/s12883-014-0217-9
PMCID: PMC4333896  PMID: 25433800
Cognitive impairment; Cerebrovascular disorder; Neuropsychology; Event related potentials P300; Homocysteine
5.  IS LOW IRON STATUS A RISK FACTOR FOR NEURAL TUBE DEFECTS? 
Background
Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort.
Methods
Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies.
Results
No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and non-affected pregnancies (case median ferritin 16.8μg/L and hemoglobin 12.4g/dL versus 15.4μg/L and 12.3g/dL in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida)
Conclusions
We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs.
doi:10.1002/bdra.23223
PMCID: PMC4018583  PMID: 24535840
ferritin; iron; hemoglobin; neural tube defects
6.  Neural tube defects – disorders of neurulation and related embryonic processes 
Neural tube defects (NTDs) are severe congenital malformations affecting 1 in every 1000 pregnancies. ‘Open’ NTDs result from failure of primary neurulation as seen in anencephaly, myelomeningocele (open spina bifida) and craniorachischisis. Degeneration of the persistently open neural tube in utero leads to loss of neurological function below the lesion level. ‘Closed’ NTDs are skin-covered disorders of spinal cord structure, ranging from asymptomatic spina bifida occulta to severe spinal cord tethering, and usually traceable to disruption of secondary neurulation. ‘Herniation’ NTDs are those in which meninges, with or without brain or spinal cord tissue, become exteriorised through a pathological opening in the skull or vertebral column (e.g. encephalocele and meningocele). NTDs have multifactorial etiology, with genes and environmental factors interacting to determine individual risk of malformation. While over 200 mutant genes cause open NTDs in mice, much less is known about the genetic causation of human NTDs. Recent evidence has implicated genes of the planar cell polarity signalling pathway in a proportion of cases. The embryonic development of NTDs is complex, with diverse cellular and molecular mechanisms operating at different levels of the body axis. Molecular regulatory events include the BMP and Sonic hedgehog pathways which have been implicated in control of neural plate bending. Primary prevention of NTDs has been implemented clinically following the demonstration that folic acid, when taken as a peri-conceptional supplement, can prevent many cases. Not all NTDs respond to folic acid, however, and adjunct therapies are required for prevention of this folic acid-resistant category.
doi:10.1002/wdev.71
PMCID: PMC4023228  PMID: 24009034
7.  Clinical spectrum of neural tube defects with special reference to karyotyping study 
Background:
Neural tube defects are common congenital malformations of the central nervous system. Despite years of intensive epidemiological, clinical, and experimental research, the exact etiology of NTD remains rather complex and poorly understood. The present study attempted to look into the association of occurrence of NTD with reference to folic acid levels, along with karyotyping status.
Materials and Methods:
Detailed history was taken with emphasis on age of the baby and mother, parity, antenatal folic acid intake. Five milliliters of blood was drawn from all the babies and their mothers and divided equally in preheparinized vials (for karyotyping) and plain vials (for folic acid estimation). The total duration was 2 years.
Results:
The total number (n) in the study group was 75. The folic acid level was less in affected babies and their mother when compared to matched controls. Chromosomal defect was observed in nine of the 75 patients. Karyotyping defects were higher in children born to mothers of the age group 31-40 years and when their birth order was second.
Conclusion:
Folic acid supplementation needs to be continued to prevent the occurrence of NTD, and the perinatal identification of NTD should alert one to the possibility of chromosomal abnormalities and prompt a thorough cytogenetic investigation and genetic counseling.
doi:10.4103/1817-1745.102560
PMCID: PMC3519089  PMID: 23248680
Chromosomal defect; folic acid; neural tube defects; karyotyping
8.  Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study 
PLoS Medicine  2009;6(5):e1000061.
In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth.
Background
Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.
Methods and Findings
In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics.
Conclusions
Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.
Editors' Summary
Background
Most pregnancies last about 40 weeks, but sometimes the new family member arrives early. Every year, half a million babies in the United States (12.5% of all babies) are born prematurely (before 37 completed weeks of pregnancy). Sadly, premature babies are more likely to die than full-term babies and many have short- and/or long-term health problems. Premature babies often have breathing problems, they are susceptible to life-threatening infections, and they are more likely to have learning and developmental disabilities than those born on time. The severity of these health problems depends on the degree of prematurity—preterm babies born between 34 and 36 weeks of pregnancy rarely develop severe disabilities, but a quarter of babies born before 28 weeks of pregnancy develop serious lasting disabilities and half have learning and behavioral problems. Although doctors have identified some risk factors for early delivery (for example, smoking), it is impossible to predict who will have an early birth and there is no effective way to prevent preterm births.
Why Was This Study Done?
Some researchers think that folate supplements may prevent preterm births. Folate (folic acid), a vitamin found in leafy green vegetables, fruits, and dried beans, helps to prevent neural tube birth defects. Consequently, women are encouraged to take folic acid supplements throughout (and preferably before) pregnancy and many governments now mandate that bread, pasta, and other grain products be fortified with folic acid to help women get sufficient folate. There is some evidence that women who deliver early have less folate in their blood than women who deliver at term. Furthermore, folate supplementation during pregnancy has increased the length of pregnancy in some but not all clinical trials. A possible explanation for these mixed results is that the duration of pregnancy reflects conditions in the earliest stages of pregnancy or before conception and that folate supplementation needs to start before conception to reduce the risk of preterm birth. In this study, the researchers test this idea by analyzing data collected from nearly 35,000 pregnant women enrolled in a study that was originally designed to investigate screening for Down's syndrome.
What Did the Researchers Do and Find?
During the first three months of their pregnancy, the women were asked whether they had taken folate supplements before conception. The duration of each pregnancy was estimated from ultrasound measurements taken early in the pregnancy and from the time of delivery. During the study, 1,658 women had spontaneous preterm deliveries before 37 weeks and 160 delivered before 32 weeks. After allowing for other maternal characteristics that might have affected the likelihood of preterm delivery, the risk of spontaneous preterm delivery between 20 and 28 weeks was 70% lower in women who took folate supplements for more than a year before becoming pregnant than in women who didn't take a supplement. Long-term folate supplementation also reduced the risk of preterm delivery between 28 and 32 weeks by 50% but did not affect the risk of preterm birth beyond 32 weeks. Folate supplementation for less than a year before conception did not reduce the risk of preterm birth, and folate supplementation was not associated with any other complications of pregnancy.
What Do These Findings Mean?
These findings show that folate supplementation for a year or more before conception is associated with a 50%–70% decrease in early (but not late) spontaneous preterm births and that the longer a woman takes folate supplements before becoming pregnant, the lower her risk of a preterm birth. Although the researchers allowed for maternal characteristics that might have affected the duration of pregnancy, it is possible that folate supplementation may not be responsible for the reduction in preterm birth risk seen in this study. For example, taking folate supplements may be a marker of healthy behavior and the women taking the supplements might have been doing something else that was reducing their risk of preterm birth. However, despite this and other limitations of this study, these findings suggest that long-term folate supplementation before conception is worth investigating further as a potential way to prevent preterm births.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000061.
This study is further discussed in a PLoS Medicine Perspective by Nicholas Fisk
The MedlinePlus encyclopedia contains a page on premature babies (in English and Spanish); MedlinePlus provides links to other information on premature babies (in English and Spanish)
The US National Institute of Child Health and Human Development provides information on preterm labor and birth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth and on folic acid (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Office of Dietary Supplements has a fact sheet on folate
doi:10.1371/journal.pmed.1000061
PMCID: PMC2671168  PMID: 19434228
9.  Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events 
OBJECTIVE: To establish guidelines for the screening and treatment of hyperhomocysteinemia in the investigation and management of coronary artery disease (CAD). OPTIONS: Measurement of plasma total homocysteine (tHcy) levels in the fasting state or 4-6 hours after oral methionine load; vitamin supplementation with folic acid and vitamins B6 and B12; adherence to the recommended daily allowance of dietary sources of folate and vitamins B6 and B12. OUTCOMES: This article reviews the available evidence on the association between plasma tHcy levels and CAD and the effect of lowering tHcy levels through vitamin supplementation or dietary intake. EVIDENCE: MEDLINE was searched for relevant English-language articles published from January 1966 to June 1999; also reviewed were additional articles identified from the bibliographies. BENEFITS, HARMS AND COSTS: Cardiovascular disease is the leading cause of death in Canada. Homocysteine, generated in the metabolism of methionine, may have a role in the development of cardiovascular disease. The prevalence of hyperhomocysteinemia in the general population is between 5% and 10% and may be as high as 30%-40% in the elderly population. If population-based studies are correct, tHcy may be responsible for up to 10% of CAD events and thus may represent an important and potentially modifiable risk factor for cardiovascular disease. Laboratory testing for tHcy is currently restricted to research centres, and costs range from $30 to $50 per person. Newer, less costly techniques have been developed and should become readily available with time. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: Although there is insufficient evidence to recommend the screening or management of hyperhomocysteinemia at present (grade C recommendation), adherence to recommended daily allowance of dietary sources of folate and vitamins B12 and B6 should be encouraged. If elevated tHcy levels are discovered, vitamin deficiency should be ruled out to allow specific treatment and prevention of complications, such as neurological sequelae due to vitamin B12 deficiency. Experts in the field advocate treatment of elevated tHcy levels in high-risk people, such as those with a personal or family history of premature atherosclerosis or a predisposition to develop hyperhomocysteinemia. Definitive guidelines for the management of hyperhomocysteinemia await the completion of randomized trials to establish the effect of vitamin supplementation on CAD events. VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care. SPONSORS: The Canadian Task Force on Preventive Health Care is funded through a partnership between the Provincial and Territorial Ministries of Health and Health Canada.
PMCID: PMC1232546  PMID: 10920726
10.  Neural Tube Defects, Folic Acid and Methylation 
Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.
doi:10.3390/ijerph10094352
PMCID: PMC3799525  PMID: 24048206
neural tube defects; folate; methylation; choline; methionine; homocysteine; MTHFR; B12 vitamin
11.  Plasma Aβ, homocysteine, and cognition 
Neurology  2009;72(3):268-272.
Background:
Amyloid-beta protein (Aβ) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Aβ levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation–induced reduction of tHcy influences plasma Aβ levels in the Vitamin Intervention in Stroke Prevention (VISP) study.
Methods:
Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Aβ with 40 (Aβ40) and 42 (Aβ42) amino acids were measured at baseline and at the 2-year visit.
Results:
tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Aβ40 but not Aβ42 concentrations. There was no difference in the change in Aβ40, Aβ42 (p = 0.40, p = 0.35), or the Aβ42/Aβ40 ratio over time (p = 0.86) between treatment groups. Aβ measures were not associated with cognitive change.
Conclusions:
This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Aβ40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Aβ, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Aβ40, they may be regulated by independent mechanisms.
GLOSSARY
= amyloid-beta;
= Alzheimer disease;
= body mass index;
= diastolic blood pressure;
= Mini-Mental State Examination;
= modified Rankin Scale;
= NIH Stroke Scale;
= systolic blood pressure;
= total homocysteine;
= Vitamin Intervention in Stroke Prevention study.
doi:10.1212/01.wnl.0000339486.63862.db
PMCID: PMC2677526  PMID: 19153374
12.  Red blood cell folate levels in pregnant women with a history of mood disorders: a case series 
Objective
Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906nmol/L have been associated with the lowest risk of having an NTD affected pregnancy. Mood disorders (e.g. depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against NTDs. While previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder.
Methods
We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161days gestation) from n=24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birthweight.
Results
Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range: 362 –1105nmol/L). Only 12.5% (n=3) of the women had an RBC folate concentrations >906nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birthweights ranged from 2296g to 4819g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas).
Conclusion
Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders.
doi:10.1002/bdra.23144
PMCID: PMC3951991  PMID: 23760977 CAMSID: cams3096
folic acid; folate; pregnancy; mood disorders; depression; birth defects; congenital abnormalities
13.  Neural Tube Defects and Maternal Intake of Micronutrients Related to One-Carbon Metabolism or Antioxidant Activity 
Background
Maternal nutritional status has been evaluated to clarify its role in development of neural tube defects (NTDs). Maternal folate intake during pregnancy has been closely evaluated for its association with NTDs.
Objective
The study objective was to examine associations between NTDs and other dietary periconceptional micronutrient intake, particularly nutrients involved in one-carbon metabolism or antioxidant activity.
Design
Using data from the National Birth Defects Prevention Study, 1997–2005, logistic regression models were used to estimate the relative risk of NTDs based on maternal micronutrient intake.
Results
Results were stratified according to folic acid supplement use, race/ethnicity, and maternal body mass index. Analyses included 954 cases (300 with anencephaly, 654 with spina bifida) and 6268 controls. Higher intakes of folate, thiamin, betaine, iron, and vitamin A were associated with decreased risk of anencephaly among some ethnic and clinical groups. In some groups, higher intakes of thiamin, riboflavin, vitamin B6, vitamin C, vitamin E, niacin, and retinol were associated with decreased risk of spina bifida.
Conclusion
In addition to folic acid, other micronutrients, including thiamin, betaine, riboflavin, vitamin B6, vitamin C, vitamin E, niacin, iron, retinol, and vitamin A, may decrease the risk of NTD occurrence.
doi:10.1002/bdra.23068
PMCID: PMC3518275  PMID: 22933447
Dietary periconceptional micronutrients; maternal nutrition; National Birth Defects Prevention Study; neural tube defects; one-carbon metabolism
14.  Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study 
Diabetologia  2007;51(1):29-38.
Aims/hypothesis
Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B12, folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years.
Methods
In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B12, tHcy and methylmalonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-R]) at 6 years.
Results
Two-thirds of mothers had low vitamin B12 (<150 pmol/l), 90% had high MMA (>0.26 μmol/l) and 30% had raised tHcy concentrations (>10 μmol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p < 0.01). Low maternal vitamin B12 (18 weeks; p = 0.03) predicted higher HOMA-R in the children. The offspring of mothers with a combination of high folate and low vitamin B12 concentrations were the most insulin resistant.
Conclusions/interpretation
Low maternal vitamin B12 and high folate status may contribute to the epidemic of adiposity and type 2 diabetes in India.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0793-y) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-007-0793-y
PMCID: PMC2100429  PMID: 17851649
Adiposity; Folate; Insulin resistance; Maternal nutrition; Offspring; Pregnancy; Vitamin B12
15.  Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke 
PLoS Genetics  2014;10(3):e1004214.
Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10−63], CBS [p = 3.15×10−26], CPS1 [p = 9.10×10−13], ALDH1L1 [p = 7.3×10−13] and PSPH [p = 1.17×10−16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
Author Summary
Elevated homocysteine (tHcy) is strongly associated with risk for common disorders such as stroke, cardiovascular disease and Alzheimer disease. Lowering tHcy levels has proven to have variable success in reducing clinical risk, so the question remains, “Are we correctly targeting these disorders by lowering tHcy?” Understanding folate one-carbon metabolism pathway (FOCM) genetic variation will aid us in developing new targets for therapy. The FOCM is essential in regulation of the epigenome, which controls genes in ways beyond nucleotide sequence. We present data generated from stroke-only and general populations where we identify strong association of genetic risk factors for variation in one-carbon metabolism function, characterized by the post-methionine load test. We show that GNMT harbors genetic and epigenetic differences that influence gene function, which may have downstream effects on the epigenome of the cell, affecting disease risk. We developed a genetic risk score that predicts post-methionine load homocysteine levels that may be useful in clinic. Finally, we identified a novel association between ischemic stroke and ALDH1L1, which emphasizes the clinical importance of this work. Our results highlight the importance of a concerted effort to target the FOCM (beyond tHcy) and parallel pathways in future pharmacogenetic work using the genetic variation we describe here.
doi:10.1371/journal.pgen.1004214
PMCID: PMC3961178  PMID: 24651765
16.  How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study 
Background
In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate.
Methods
The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55).
Results
Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, P < 0.001) and RBC (r = 0.36, P < 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 μg/d (3rd and 4th quartile).
Conclusion
Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 μg.
doi:10.1186/1471-2393-7-25
PMCID: PMC2231404  PMID: 17961229
17.  Maternal Folate and Vitamin B12 Status and Neural Tube Defects in Northern Iran: A Case Control Study 
Iranian Journal of Pediatrics  2010;20(2):167-173.
Objective
This study was conducted to determine the serum level of folic acid and vitamin B12 in neural tube defects pregnancies (NTD) and healthy controls in Northern Iran.
Methods
This case-control study was performed on women with neural tube defects pregnancies and controls with unaffected pregnancies in Northern Iran during 2006. Twenty three pregnant women whose pregnancies were diagnosed as NTD by a second-trimester ultrasonographic examination were recruited as cases. The control group (n=23) consisted of women who were selected among socio-economic status (SES) matched women who had a normal targeted ultrasound during the second trimester with documented normal fet al outcome. Fetal NTD was suspected with targeted second-trimester ultrasound during the 16th week of gestation and confirmed with high maternal serum α-fetoprotein levels. Folate, vitamin B12, homocysteine and alpha fetoprotein were evaluated after target ultrasonography.
Findings
Serum alpha fetoprotein level (mean±SD) in cases and controls was 120.2±64.1 and 50±33.5 iu/ml, respectively (P<0.05). The mean±SD folate in cases and controls was 8.4±4.2 versus 9.3±4.2 ng/ml, respectively. This difference was not significant. Folate deficiency was found in 30.4% of the cases and 13% of the controls (OR=2.9, 95%: 0.54–19.8). Vitamin B12 deficiency was found in 13% of cases and 17.7% of the controls (OR=0.7, 95%: 0.1-4.9).
Conclusion
This study showed that the probability of having a newborn with NTDs in maternal folate deficiency is three times higher than with normal folate in Northern Iran.
PMCID: PMC3446032  PMID: 23056699
Neural tube defects; Folic acid deficiency; Vitamin B12; Pregnancy; Iran
18.  Gene–environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function 
Human Molecular Genetics  2008;17(23):3675-3685.
Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp2H) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp2H embryos, demonstrating a gene–environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation.
doi:10.1093/hmg/ddn262
PMCID: PMC2581426  PMID: 18753144
19.  Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications 
Gut  1999;45(3):389-394.
BACKGROUND—Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD.
AIMS—To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD.
METHODS—Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC).
RESULTS—Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B12 levels were lower in patients with IBD irrespective of MTHFR genotype.
CONCLUSIONS—There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B12 therapy to protect against the thromboembolic complications of raised tHcy.


Keywords: methylenetetrahydrofolate reductase; C677T variant; inflammatory bowel disease
PMCID: PMC1727640  PMID: 10446107
20.  Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia 
Epigenetics  2013;8(3):303-316.
The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR’s) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.
doi:10.4161/epi.23988
PMCID: PMC3669122  PMID: 23417011
FOLR1; PCFT; RFC1 80G>A; homocysteine; tissue-specific DNA methylation; GpG island; NTD
21.  Homocysteine, vitamins, and coronary artery disease. Comprehensive review of the literature. 
Canadian Family Physician  2000;46:2236-2245.
OBJECTIVE: To summarize results of clinical trials investigating the role of homocysteine (tHcy) as a risk factor for coronary artery disease (CAD) and the role of vitamin therapy (folic acid and vitamins B6 and B12) in primary and secondary prevention of CAD. QUALITY OF EVIDENCE: MEDLINE was searched from January 1976 to January 1999 to locate cross-sectional, retrospective and prospective cohort studies and meta-analyses on CAD using the MeSH words homocysteine, folic acid, vitamins B6 and B12, and coronary artery or heart disease. MAIN MESSAGE: Elevated tHcy levels are prevalent; most retrospective and cross-sectional studies show an association with increased risk of CAD. Results from recent prospective studies are less consistent. Folic acid, alone or with vitamins B6 and B12, reduces tHcy concentrations in the blood. Results from ongoing randomized controlled trials could determine the effect of vitamins B6 and B12 and folic acid supplementation on CAD-related morbidity and mortality and could indicate whether routine supplementation with these vitamins should be advocated. Before mass screening for tHcy can be done, the tHcy assay must be standardized. CONCLUSION: The role of homocysteine and vitamins B6 and B12 in managing CAD is unclear. Routine screening is not recommended.
PMCID: PMC2145064  PMID: 11143583
22.  Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts 
Objectives
Though toxicological experiments demonstrate the teratogenicity of organic solvents in animal models, epidemiologic studies have reported inconsistent results. Using data from the population-based National Birth Defects Prevention Study, we examined the relation between maternal occupational exposure to aromatic solvents, chlorinated solvents and Stoddard solvent during early pregnancy and neural tube defects (NTDs) and orofacial clefts (OFCs).
Methods
Cases of NTDs (anencephaly, spina bifida and encephalocele) and OFCs (cleft lip ± cleft palate and cleft palate alone) delivered between 1997 and 2002 were identified by birth defect surveillance registries in 8 states; non-malformed control infants were selected using birth certificates or hospital records. Maternal solvent exposure was estimated by industrial hygienist review of self-reported occupational histories in combination with a literature-derived exposure database. Odds ratios (OR) and 95% confidence intervals (CI) for the association between solvent class and each birth defect group and component phenotype were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, folic acid supplement use and smoking.
Results
The prevalence of exposure to any solvent among mothers of NTD cases (n=511), OFC cases (n=1163) and controls (n=2977) was 13.1%, 9.6% and 8.2%, respectively. Exposure to chlorinated solvents was associated with increased odds of NTDs (OR=1.96; CI=1.34, 2.87), especially spina bifida (OR=2.26; CI=1.44, 3.53). No solvent class was strongly associated with OFCs in these data.
Conclusions
Our findings suggest that maternal occupational exposure to chlorinated solvents during early pregnancy is positively associated with the prevalence of NTDs in offspring.
doi:10.1136/oemed-2011-100245
PMCID: PMC3719396  PMID: 22447643
congenital abnormalities; occupational exposure; solvents
23.  Potential Prevention of Neural Tube Defects by Assessment of Women of Childbearing Age Through Monitoring of Folate 
Therapeutic drug monitoring  2002;24(5):628-630.
Summary
Background
Three quarters of neural tube defects (NTD) can be prevented by sufficient dietary folate supplementation. Despite this knowledge, most women do not supplement their diet effectively. Red cell folate concentrations correlate with the risk of NTD, and levels of less than 900 nM are associated with an increased risk of these serious congenital anomalies.
Objective
Laboratory tests to assess anemia include testing for folate. This study was conducted to estimate the potential benefits of informing women of reproductive age who are unaware of their low folate levels, uncovered in their anemia tests.
Methods
The number of Ontario women of reproductive age who undergo folate tests and are at an increased risk of NTD was calculated. In addition, the authors calculated the number of NTD cases that could have been prevented if these women were informed of the possible consequences of their low folate levels should they become pregnant.
Results
In 1998, red cell folate concentrations were measured in 23,109 women of childbearing age (15–45 y). Approximately half of the women [n = 11,392 (49.3%)] had folate levels below 900 nM and thus were at an increased risk of giving birth to a child with NTD should they have become pregnant. Their overall mean relative risk (RR) of NTD was 1.95, or 1:512 births. If they would have been informed of this risk and subsequently increased their consumption of folate before becoming pregnant, 22.3 cases of NTD per year could have possibly been prevented at no extra cost, since the folic acid results were a part of investigational blood tests performed for another reason (anemia).
Conclusions
Women of reproductive age who are being evaluated for the cause of anemia and have low red cell folate results constitute a high-risk group for NTD in their children. These women should be informed of the increased risk and of methods of dietary folate supplementation.
PMCID: PMC3635838  PMID: 12352934
Folic acid; Pregnancy; Pregnancy outcome; Dietary supplements; Neural tube defects; Preventative health services; Primary prevention
24.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
25.  Association between inhibited binding of folic acid to folate receptor α in maternal serum and folate-related birth defects in Norway 
Human Reproduction (Oxford, England)  2011;26(8):2232-2238.
BACKGROUND
Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures.
METHODS
We conducted a nested case–control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n= 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n= 221). The inhibition of folic acid binding to FRα was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors.
RESULTS
There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0–1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FRα (CL/P aOR = 0.7, 95% CI 0.6–1.0; CPO aOR = 1.1, 95% CI 0.8–1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FRα.
CONCLUSIONS
Inhibition of folic acid binding to FRα in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts.
doi:10.1093/humrep/der144
PMCID: PMC3137385  PMID: 21576080
neural tube defects; oral facial clefts; folic acid; folate receptor; maternal autoantibodies

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